Sweet taste receptor antagonist compositions

ABSTRACT

The present disclosure relates to compositions comprising gymnemic acid, together with a form of zinc to block the unpleasant bitter taste of gymnemic acid as well as to extend the sweet taste blocking properties of gymnemic acid, resulting in palatable compositions for delivery to the oral cavity to block sweet taste receptors located therein. The present disclosure also relates to methods of reducing sugar consumption and reducing calorie intake via administration of such compositions to a subject.

PRIORITY DATA

This application is a continuation of U.S. application Ser. No.15/423,212, filed Feb. 2, 2017, which is a continuation of U.S.application Ser. No. 15/194,411, filed Jun. 27, 2016, now issued as U.S.Pat. No. 9,585,905, which is a continuation of U.S. application Ser. No.14/738,326, filed Jun. 12, 2015, now issued as U.S. Pat. No. 9,421,217,which claims priority, pursuant to 35 U.S.C. § 119(e), to U.S.Provisional Patent Application Ser. No. 62/011,096, filed Jun. 12, 2014,and U.S. Provisional Patent Application Ser. No. 62/025,725, filed Jul.17, 2014, the contents of each of which are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present disclosure relates to compositions comprising gymnemic acid,together with a form of zinc to block the unpleasant bitter taste ofgymnemic acid as well as to extend the sweet taste blocking propertiesof gymnemic acid, resulting in palatable compositions for delivery tothe oral cavity to block sweet taste receptors located therein. Thepresent disclosure also relates to methods of reducing sugar consumptionand reducing calorie intake via administration of such compositions to asubject.

BACKGROUND OF THE INVENTION

Gymnemic acid is extracted from Gymnema sylvestre, a woody climbingplant native to India, Africa, and. China. Gymnemic acid is a dietarysupplement sold worldwide, primarily in encapsulated forms. (See Ogawaet al., J. Food Hygienic Soc Japan (2004) 45:8-18) Gymnemic acid isknown to temporarily block the sensation of sweet taste when applieddirectly to the oral cavity. (See Kurihara, 1969 and Sanematsu, J. Biol.Chem. (2014) 289:25711-25720). Studies have shown that subjects givengymnemic acid consume fewer calories than subjects given a placebo (SeeBrala et al., Physiol. Behav. (1983) 30:1-9). However, gymnemic acid isknown to have an intense bitter taste that is unpalatable to humans.(See, for example, U.S. Publication No. 2004/007180).

Traditionally, in the field of flavor science, one would add a sweetenersuch as sucrose to a composition to mask the bitter taste of anessential ingredient. Intensely bitter ingredients would require largeramounts of sucrose or perhaps a more intense artificial sweetener suchas sucralose to mask the bitterness. However, these traditional bitterblocking methods do not work to reduce the bitter taste of gymnemicacid, as a result of gymnemic acid's sweet taste blocking property.Moreover, the use of an intense natural or artificial sweetener caninterfere with the desired sweet blocking activity of the gymnemic acid,as both sweeteners and gymnemic acid interact and bind with sweet tastereceptors (Sanematsu, J. Biol. Chem. (2014) 289:2571-25720).

It is also common in the field of flavor science, when working with acomposition containing a bitter ingredient, to prepare an encapsulatedor tablet dosage form that is intended to be immediately swallowed. Thisapproach avoids any bitterness problem because the bitter ingredientnever directly contacts the oral cavity. However, such a dosage form isnot feasible for a composition containing gymnemic acid, which isintended to directly contact the oral cavity and tongue, and then beswallowed.

For more than a decade, attempts have been made to develop a dietproduct that delivers Gymnema directly into the oral cavity. However,due to the inability of known flavor science to effectively eliminatethe intense bitterness of Gymnema, these attempts have failed. One suchattempt is discussed in U.S. Publication No. 2004/007180 which describesa lozenge combining Gymnema leaf extract with a de-bittering agent,disclosing the bitter masking agent as “Comax Flavors #2588E17379.”Sugarest™ gum, manufactured by Genotec Nutritionals, Inc. was marketedto temporarily block sweet taste receptors for 20-30 minutes. (PressRelease, MM2 Group, Inc., MM2 Group's Sugarest™ Featured on TV News inPhiladelphia (Apr. 12, 2007), available athttp://www.pmewswirc.corninews-releases/mm2-groups-sugaresttm-featured-on-tv-news-in-phitadelphia-58283722.html).The product failed and has not been available for many years.

Supresalin is a composition containing gymnemic acids alleging to reducesugar cravings for approximately 30 minutes.(http://supresalin.com/faqs/). Sugar Suppress 60 is another productcontaining gymnemic acids that claims to reduce calorie consumption andpromote weight loss. However, this product is intensely bitter andunpalatable. After many failed attempts, there remains a need for apalatable, non-bitter composition of gymnemic acid, in a lingualdelivery form, that fully blocks sweet taste for an extended period oftime.

SUMMARY OF THE INVENTION

Described herein is a composition comprising gymnemic acid, togetherwith a form of zinc to block the unpleasant bitter taste of gymnemicacid as well as to extend the sweet taste blocking properties ofgymnemic acid, resulting in palatable compositions intended to directlycontact the oral cavity to block sweet taste receptors located therein.As the sweet taste blockade effect of gymnemic acid requires the agentto remain in the oral cavity, there is a need for an effective means toreduce the bitter unpalatable taste of gymnemic acid during its deliveryto the oral cavity. This need is met by the lingual delivery forms,compositions, and methodologies of the present disclosure, whichpreferably allow for delivery of gymnemic acid to the oral cavitytogether with a form of zinc, blocking the bitter taste of gymnemicacid.

In general and according to certain embodiments, the lingual deliveryforms and compositions of the present disclosure deliver gymnemic acid,together with a form of zinc, to the sweet taste receptors of thetongue, resulting in exceptional durations of sweetness blockade whilesimultaneously reducing or eliminating its bitter taste duringapplication.

The present invention may be directed to a lingual delivery formcomprising gymnemic acid and at least one form of zinc. The lingualdelivery may include, but is not limited to, a lozenge, an orallydisintegrating tablet, an orally dispersible tablet, a troche, a hardcandy, a soft candy, a jelly, a gum, an edible film, an orallydissolvable film, a wafer, a drop, an oral spray, a liquid, a powder andcombinations thereof. The disintegration time of the orallydisintegrating tablet may be in the range of from about 30 seconds toabout 5 minutes.

The form of zinc may include, but is not limited to, zinc acetate, zinccarbonate, zinc chloride, zinc citrate, zinc gluconate, zinc sulfate,zinc hydrosulfite, zinc bisulfite, zinc oxide, zinc halide, zinchydride, zinc carbide, and combinations thereof. Preferably, the form ofzinc is a GRAS (Generally Recognized as Safe,fda.gov/Food/IngredientsPackagingLabeling/GRAS/) approved zinc salt,most preferably zinc gluconate.

The gymnemic acid may be present as an inorganic salt of gymnemic acid,an organic salt of gymnemic acid, a cyclodextrin complex of gymnemicacid, a cryptand complex of gymnemic acid, a hydrate of gymnemic acid, asolvate of gymnemic acid, and combinations thereof. The solvate ofgymnemic acid may include ethanol solvates of gymnemic acid.

The lingual delivery form may further comprise mint.

The lingual delivery form may further comprise a bitter taste inhibitor.The bitter taste inhibitor may include, but is not limited to, sodiumsalt, a lipoprotein, and combinations thereof.

The lingual delivery form may further comprise at least one sour tasteinhibitor. The sour taste inhibitor may be miraculin.

The present inventor provides methods of using the present lingualdelivery forms and compositions. The present invention provides a methodof reducing sugar consumption, comprising administering the compositionand lingual delivery forms of the present invention to a subject.Moreover, the present invention provides a method of reducing calorieintake, comprising administering the composition and lingual deliveryforms to a subject, as well as a method of reducing dental caries,comprising administering the composition and lingual delivery forms to asubject.

DETAILED DESCRIPTION OF THE INVENTION

The following is a detailed description of the invention provided to aidthose skilled in the art in practicing the present invention. Those ofordinary skill in the art may make modifications and variations in theembodiments described herein without departing from the spirit or scopeof the present invention. Unless otherwise defined, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. The terminology used in the description of the invention hereinis for describing particular embodiments only and is not intended to belimiting of the invention. All publications, patent applications,patents, figures and other references mentioned herein are expresslyincorporated by reference in their entirety.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a compound” includes a plurality of compounds. In thisspecification and in the claims that follow, reference will be made to anumber of terms that shall be defined to have the following meaningsunless a contrary intention is apparent.

It must also be noted that ratios, concentrations, amounts, and othernumerical data may be expressed herein in a range of formats. It is tobe understood that such a range of formats is used for convenience andbrevity, and thus, should be interpreted in a flexible manner to includenot only the numerical values explicitly recited as the limits of therange, but also to include all the individual numerical values orsub-ranges encompassed within that range as if each numerical value andsub-range is explicitly recited. To illustrate, a concentration range of“about 0.1% to about 5%” should be interpreted to include not only theexplicitly recited concentration of about 0.1 wt % to about 5 wt %, butalso include individual concentrations (e.g., 1%, 2%, 3%, and 4%) andthe sub-ranges (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within theindicated range. In an embodiment, the term “about” can includetraditional rounding according to significant figures of the numericalvalue. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x’ toabout ‘y’”.

As used herein, the phrase “sweetness blockade” is defined as theattenuation of the perceptible sweetness of a food or beverage or othersubstance introduced into the oral cavity. Sweetness blockade and sweettaste block are synonymous.

As used herein, the phrase “reduced bitter taste” is defined as thereduction of the bitter taste associated with a compound (e.g., gymnemicacid). In certain embodiments, the reduced bitter taste is a reductionof about 50% or more, about 75% or more, about 85% or more, about 90% ormore, about 95% or more, or about 99% or more. As used herein, thephrase “eliminate bitter taste” is defined as the reduction of thebitter taste associated with a compound (e.g., gymnemic acid) by about100%.

Gymnemic acid is not selective in its sweetness blockade. Therefore, anyfood or drink or other substance containing sweet tastants which isingested or introduced into the oral cavity during the period followingdelivery of gymnemic acid to the oral cavity do not taste sweet or theirsweet flavor is markedly diminished. Moreover, the presence of anybitter or sour flavors in such food or drink is perceived as beingamplified since bitter and sour flavors are no longer masked by thesweet flavors. Use of gymnemic acid through delivery to the oral cavity,including the tongue, stops cravings for sweet tastants in food ordrink, resulting in a decreased consumption of such high-calorie foods.The link between sweetness perception and choice of sweet foods forconsumption is known. (See Brala et al., Physiol. Behav. (1983) 30:1-9).

A drawback to using gymnemic acid in this manner is that gymnemic acidis known to have an unpleasant and intense bitter taste that isunpalatable to humans. Another drawback is that while gymnemic acidblocks the sensation of sweet taste, such effect is transitory and lastsfor only a short period of time. Thus, there exists a continuing needfor improved gymnemic acid-based compositions that can block thesensation of sweet taste for longer periods of time while reducing oreliminating the bitter taste of the gymnemic acid. Moreover, thereexists a need for an effective means to greatly reduce or eliminate theintense bitter and unpalatable taste of gymnemic acid during itsdelivery to the oral cavity.

Much is known about sweet taste receptors. Sweetness is one of the fiveprimary categories of taste sensed by humans. Receptors initiating thissensation are located in one of three kinds of taste bud cells known asType I, Type II, and Type III, which are located in taste buds locatedprimarily on the tongue, but are also found on the soft palate and otherregions of the oral cavity. Sweet taste receptors are located indifferent subsets of Type II taste bud cells. Sweetness sensing tastebud cells express a single heterodimeric receptor identified asT1R2/T1R3.

In contrast, bitter taste transduction mechanisms are complex and notfully understood. It is known that human bitter taste is initiated byactivation of 26 T2R receptors which are generally accepted to exist asa mixture of homo-dimeric and hetero-dimeric species in bitter-sensitivetaste bud cells, thus providing a total of 346 possible functionalreceptors, where the relative numbers of these dimeric species arethought to vary from person to person. (See C. Kuhn et al., Chem. Senses2010, 35:395-406). Such diversity between people demonstrates thecomplexity of bitter taste in contrast to other tastes such as sweet andsour. Furthermore, given that gymnemic acid is a complex mixture of over20 unique triterpenoid saponins (see Imoto et al., J Chromatography(1991) 557:383-389), which all may have different bitter tasteattributes, blocking the bitter taste of gymnemic acid presents asignificant challenge.

Given that there 26 T2R bitter receptors responsible for sensing bitterstimuli, blocking the associated bitterness is very difficult whenmultiple receptors are activated. The bitter response created by acomplex mixture of molecules contained in an herbal extract, such as acomposition containing gymnemic acid, would be expected to trigger alarge number of individual bitter receptors. It would thus be expectedthat a single agent with bitter blocking properties would not completelyabolish the bitter taste of gymnemic acid.

It is known that zinc has some ability to block both sweet and bittertastes. The utilization of zinc salts has been described in previouspublications as a taste modifier. (Keast, JFS (2003) 68:1871-1877).While gymnemic acid inhibits the sweetness of all natural and artificialsweeteners, zinc salts are selective in their inhibition and are notuniversal inhibitors. For example, Keast and Breslin have demonstratedthat zinc sulfate is an effective bitterness inhibitor against quinine,denatonium benzoate, and tetralone but has no significant bitternessinhibitory activity against sucrose octaacetate, pseudoephedrine, anddextromethorphan. (Keast, JFS (2003) 68:1871-1877) For further example,it has been observed that ZnSO₄ inhibits the bitterness of quininehydrochloride (QHC1) by up to 70% (Keast, JFS (2003) 68:1871-1877).However it must be noted that zinc may only interfere with themechanism(s) responsible for bitter taste transduction of a subset ofbitter compounds, of which there are thousands, rather than all bittercompounds. (Keast, JFS (2003) 68:1871-1877).

Zinc alone is not anticipated to be fully effective as a taste-modifier,and is not sufficient to provide a palatable composition. To becompletely effective, the zinc is traditionally accompanied byadditional flavor masking agents such as sucrose, fructose, sorbitol,xylitol, artificial sweeteners and/or flavoring compositions (i.e.,fruit or citrus flavors). Moreover, zinc itself is known to have ametallic, chalky, astringent objectionable aftertaste common to metallicions, and an additional flavor masking agent is also needed to mask theunpleasant taste of the zinc. Thus, zinc is not considered to be asingle agent that may be used to fully block a bitter tastingingredient.

Nonetheless, it was surprisingly found that the addition of a form ofzinc to a gymnemic acid extract not only results in a composition thatdoes not require any further taste-masking agents to taste palatable andblock sweet taste, but the duration of the sweetness blockage isextended to at least 60-80 minutes, greater than the duration ofsweetness blockade obtains with gymnemic acid alone.

Through compositions of the present invention, it has been unexpectedlyfound that when gymnemic acid is combined with zinc, the bitter taste ofthe gymnemic acid is reduced and almost completely eliminated while thesweet taste blocking properties of the gymnemic acid remain effective.Moreover, it has been unexpectedly found that compositions of gymnemicacid together with a form of zinc block sweet taste in human subjectsfor a longer period of time than administration of gymnemic acid aloneor zinc alone. It has been unexpectedly found that the length of thesweetness blockade may be extended to a duration of at least 60-80minutes or longer upon the delivery to the oral cavity of compositionsthat contain a combination of gymnemic acid and a form of zinc, greaterthan the duration of sweetness blockade obtains with gymnemic acidalone.

The present invention provides delivery of gymnemic acid to the oralcavity in order to block the sensation of sweet tastants. Thus, duringthe ingestion of any sweet food or drink, the sweet tastant does notlead to the perception of sweet taste. The person or subject using thecomposition of the present invention will no longer be able toexperience the sweet taste of what they are eating or drinking orintroducing into the oral cavity, rendering most foods, drinks, andother substances unpalatable. Thus, the present invention provides acomposition which allows the user to address their cravings for sweetfoods immediately. Moreover, through more extended use, the user of thecomposition may modify their behavior because they no longer associate apleasant feeling with foods that previously tasted sweet. Thus, thepresent invention also provides methods of to reduce sugar consumptionand reduce calorie intake by a subject via administration to the subjectof the gymnemic acid-containing compositions described herein.

In general and according to certain embodiments, the lingual deliveryforms and compositions of the present disclosure deliver gymnemic acidto the sweet taste receptors of the tongue, resulting in exceptionaldurations of sweetness blockade while simultaneously reducing oreliminating gymnemic acid's bitter taste during application.

The unique and surprising performance of compositions containing bothgymnemic acid and a form of zinc provides an advantage over prior artgymnemic acid formulations, providing longer periods of sweet tasteblocking and allowing a subject to maintain the gymnemic acid-containingcomposition in the oral cavity for a longer duration withoutexperiencing gymnemic acid's unpleasant bitter flavor.

Applicants surprisingly found that application of a compositioncomprising gymnemic acid together with a form of zinc as an additionalsweetness inhibitor provided a total sweetness blockade greater than thesum of the sweetness blocking effects of zinc used individually, andgymnemic acid used individually. Synergy is defined as the cooperativeaction of discrete agencies such that the total effect is greater thanthe two or more effects taken independently.

Given the complexity of the human bitter taste receptor system with asmany as 346 functional receptors, where it is commonly found thatspecific bitterants activate multiple bitter receptors and where thereis as yet no knowledge of the specific bitterant receptors activated bygymnemic acid, the prediction of the identity of a specific bitternessinhibitor for gymnemic acid is not possible. Furthermore, forms of zincare specific in their bitterness inhibitory activity and not broadlyapplicable. Thus, it would not be expected that a combination of a formof zinc and gymnemic acid would provide full sweet-taste blockingwithout any bitter taste, let alone provide a synergistic effectincreasing the duration of the sweet taste blockade. Moreover, the lociof gymnemic acid and zinc binding to T1R2/T1R3 are not known. Withoutthis knowledge, synergy cannot be predicted.

The “form of zinc” may be in any form, such as a zinc salt. For example,the zinc form may include, but is not limited to, forms of zincgenerally recognized as safe by the U.S. FDA (“GRAS”) such as zincacetate, zinc carbonate zinc chloride, zinc gluconate, zinchydrosulfite, zinc oxide and zinc sulfate, as well as zinc halide, zinchydride, zinc carbide, zinc citrate, and zinc bisulfate, and as well asany combination thereof.

The lingual delivery forms and compositions of the present inventionprovide exceptional durations of sweetness blockade (e.g., about 30minutes or more, about 60 minutes or more, about 80 minutes or more,about 90 minutes or more, or about 120 minutes or more), whilesimultaneously reducing or eliminating the bitter taste associated withgymnemic acid. It has been unexpectedly found that the length of thesweetness blockade may be extended to longer than gymnemic acid or zincalone, for example to greater than 80 minutes, upon the delivery to theoral cavity of compositions including a combination of gymnemic acid anda form of zinc. Thus, the lingual delivery forms and compositions of thepresent invention have the ability to assist people in controlling theirconsumption of sweet foods and beverages that are high in calories.

One aspect of the present invention is a lingual delivery formcomprising gymnemic acid and a form of zinc. As used herein, the term“lingual” refers to any area of the oral cavity containing tastereceptors, including the tongue and any other location therein. The oralcavity can include the tongue, inside of the mouth, the buccal cavity,under the tongue, and the like. As used herein, the term “lingualdelivery form” refers to any solid or liquid form or vehicle that can beused to deliver gymnemic acid, the at least one additional sweet tasteinhibitor, and any other components, such as a bitter taste inhibitor ora sour taste inhibitor, to the taste receptors on the tongue as well asother taste receptors in the oral cavity of a subject.

Examples of such lingual delivery forms include, but are not limited to,lozenges, tablets, orally disintegrating tablets, orally dispersibletablets, troches, hard candies, soft candies, jellies, gums, ediblefilms, orally dissolvable films, wafers, drops, oral sprays, liquids,and powders. In certain embodiments, the subject maintains a solidlingual delivery form comprising gymnemic acid and a form of zinc in theoral cavity for about 3 to 5 minutes. In other embodiments, the subjectmaintains a liquid lingual delivery form comprising gymnemic acid and aform of zinc in the oral cavity for about 3 to 5 minutes. In certainother embodiments, the lingual delivery form is an orally disintegratingtablet having a disintegration time in the range of from about 30seconds to about 5 minutes. The disintegration time may be determinedusing the USP <2040> method for disintegration and dissolution ofdietary supplements. The parameters for this method include deionizedwater, temperature of 35°-37° Celsius, and a sample size of greater than6.

Another aspect of the present invention is a composition comprisinggymnemic acid and a form of zinc which may also further comprise atleast one additional sweet taste inhibitor, with the proviso that the atleast one additional sweet taste inhibitor is not lactisole, sodium3-(4-methoxyphenoxy) propionate, hodulcine, or ziziphin.

Yet another aspect of the present invention is a composition comprisinggymnemic acid and a form of zinc, and at least one sour taste inhibitor.

The lingual delivery forms and the compositions of the present inventioncomprise gymnemic acid. As used herein, gymnemic acid refers to extractsof the plant Gymnema sylvestre which contain one or more triterpenoidsaponins capable of inhibiting the sensation of sweet taste in a human.Also contemplated are compositions comprising gymnemic acid that includethe synthetic counterparts of these extracted triterpenoid saponinsExamples of such compounds include, but are not limited to, compounds ofFormula (I):

Wherein

R¹ R² R³ R⁴ R⁵ R⁶ Entry CAS # (C-3) (C-23) (C-16) (C-28) (C-22) (C-21) 1122168-40-5 β-D-GlcA OH OH Acetyl OH Tigloyl 2 122144-48-3 β-D-GlcA OHOH Acetyl OH (S)- Methyl- butyloyl 3 122074-65-1 β-D-GlcA OH OH OH OH(S)- Methyl- butyloyl 4 121903-96-6 β-D-GlcA OH OH OH OH Tigloyl 5121903-99-9 β-D-GlcA OH OH OH Tigloyl Tigloyl 6 121903-98-8 β-D-Glc- OHOH OH OH Tigloyl (1→6)-β-D- GlcA 7 121903-97-7 β-D-GlcA OH OH OH H OH 8131653-19-5 Structure A OH OH OH OH (S)- (see below) Methyl- butyloyl 9131653-20-8 Structure OH OH OH OH Tigloyl (see below) 10 147934-05-2β-D-GlcA OH OH Acetyl OH OH 11 147899-35-2 β-D-GlcA OH OH Tigloyl OHTigloyl 12 147899-36-3 b-D-Glc- OH OH Acetyl OH Tigloyl (1→6)-b-D- GlcA13 155023-61-3 β-D-GlcA OH OH (S)- OH OH Methyl- butyloyl 14 155023-62-4β-D-GlcA OH OH Tigloyl OH OH 15 154977-74-9 β-D-GlcA OH OH OH Tigloyl(S)- Methyl- butyloyl 16 154977-75-0 β-D-GlcA OH Tigloyl OH Tigloyl OH17 154977-76-1 β-D-GlcA OH OH OH OH Benzoyl

Structure A 18 154977-77-2 β-D-GlcA OH OH Benzoyl OH OH 19 22467-07-8 OHOH OH OH OH OH 20 121686-42-8 β-D-GlcA OH OH OH OH OH 21 42483-24-9 OHOH OH OH H H 22 62641-93-4 Acetyl Acetyl Acetyl Acetyl H H 231581276-60-9 OH OH OH OH OH (S)- Methyl- butyloyl 24 1581276-61-0 OH OHOH Acetyl OH (S)- Methyl- butyloyl 25 1581276-62-1 Acetyl Acetyl AcetylAcetyl Acetyl (S)- Methyl- butyloyl 26 1581276-63-2 OH OH OH OH OHTigloyl 27 174324-52-8 OH OH OH OH OH H 28 174324-49-3 β-D-GlcA- OH OHOH Tigloyl H (1→3)-β-D- Glc 29 174324-48-2 β-D-GlcA- OH OH OH OH H(1→3)-β-D- Glc 30 174324-50-6 β-D-GlcA OH OH OH Tigloyl H 31 174324-51-7β-D-GlcA OH OH OH OH H 32 175033-15-5 β-D-GlcA OH OH OH Acetyl Tigloyl33 174232-51-0 β-D-GlcA OH Acetyl OH OH Tigloyl 34 199618-65-0 β-D-GlcAOH OH Acetyl OH Benzoyl 35 199618-66-1 OH β-D-Xyl- OH OH H OH (1→6)-β-D-Glc- (1→6)-β- D-Glc 36 199618-67-2 OH P-D-Xyl- OH β-D-Glc- H H(1→6)-β- (1→6)-β- D-Glc- D-Glc (1→6)-β- D-Glc 37 199618-68-3 OH β-D-Xyl-OH β-D-Glc- H H (1→6)-β- (1→6)-β- D-Glc- D-Glc (1→6)-β- D-Glc 38133629-85-3 OH β-D-Glc- OH OH H H (1→6)-β- D-Glc 39 133629-80-8 OH OH OHGlc H H 40 133629-81-9 OH β-D-Glc OH β-D-Glc H H 41 133629-82-0 OH GlcOH β-D-Glc- H H (1→6)-β- D-Glc 42 133629-83-1 OH β-D-Glc- OH β-D-Glc H H(1→6)- 13-D- Glc 43 133629-84-2 OH β-D-Glc- OH β-D-Glc- H H (1→6)-β-(1→6)-β- D-Glc D-Glc 44 19942-02-0 OH OH OH OH H OH 45 23887-98-1 OH OHOH OH H H 46 117773-94-1 OH OH H OH H H 47 144721 4-84- OH OH OH OH Hα-OH 7 48 42483-24-9 OH OH OH OH H H 49 1447214-87-0 0= OH OH OH H H 501447214-89-2 0= OH OH OH H OH 51 1447214-91-6 0= OH OH OH OH H (See DiFabio etal., Molecules (2014) 19: 10956-10981).

In certain embodiments, the gymnemic acid used in the lingual deliveryforms and compositions of the present invention comprises one or morecompounds of Formula (I) above. In other embodiments, the gymnemic acidcomprises any one of or any combination of homologues of gymnemic acid,including but not limited to, GA 1 (Gymnemic Acid I), GA 2 (GymnemicAcid II), GA 3 (Gymnemic Acid III), GA 4 (Gymnemic Acid IV), and GA 34(Gymnemoside C).

The gymnemic acid used in the lingual delivery forms and compositions ofthe present invention can be of any purity, i.e., content of anycombination of terpenoid saponins, where purity is defined as theproportion of gymnemic acid to the sum of gymnemic acid and othermaterial from the Gymnema sylvestre plant. For example, the gymnemicacid used can have a purity of at least 20%, and least 30%, at least40%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least90%, or at least 99%. In certain embodiments, the purity can beexpressed in terms of either weight % or area % (AUC). Purity of thegymnemic acid may be determined by HPLC. In certain embodiments, puritymay be determined using the USP <621> HPLC methodology. Preferably, HPLCis performed using a Waters XSelect CSH C18 Column, 130A, 5 gm, 4.6mm×250 mm.

The gymnemic acid used in the lingual delivery forms and compositions ofthe present invention can be an inorganic salt, an ammonium salt, anamino salt including a polyamino salt, an organic salt, a cyclodextrincomplex, a cryptand complex, a hydrate, or a solvate of gymnemic acid,or any combination thereof. Examples of inorganic salts of gymnemic acidinclude, but are not limited to, alkali metal salts, such sodium andpotassium, alkaline earth metal salts, such as magnesium and calcium,transition metal salts, such as manganese, iron, and zinc, and rareearth metal salts, such as lanthanum, europium and terbium. Examples ofammonium salts of gymnemic acid include, but are not limited to,ammonium salts, mono-alkyl-substituted ammonium salts such as amethylammonium salt, di-alkyl-substituted ammonium salts, such as adimethylammonium salt, tri-alkyl-substituted ammonium salt, such as atrimethylammonium salt, or tetra-alkyl-substituted ammonium salts, suchas a tetramethylammonium salt. Examples of polyamino salts of gymnemicacid include, but are not limited to, are di-amino salts, such as anethylenediamine salt, tri-amino salts, such as an diethylenetriaminesalt, tetra-amino salts, such as a triethylenetetraamine salt, and otherpoly-amino salts, such as an α-polyornithine salt, an a-polylysine salt,a γ-polyornithine salt, an ε-polylysine salt, or a chitosan salt.Examples of cyclodextrin complexes of gymnemic acid include, but are notlimited to, α-cyclodextrin, β-cyclodextrin, and y-cyclodextrin complexesof gymnemic acid. Examples of solvates of gymnemic acid include ethanolsolvates of gymnemic acid and ethyl acetate solvates of gymnemic acid.In certain embodiments, the gymnemic acid can be in the form of aprotein salt with a protein having a pI of about 7 or more.

In certain embodiments of the present invention, the amino salt form ofgymnemic acid can be a mono-alkyl substituted derivative of the aminosalt form of gymnemic acid, a di-alkyl substituted derivative of theamino salt form of gymnemic acid, or a tri-alkyl substituted derivativeof the amino salt form of gymnemic acid. In other embodiments of thepresent invention, the di-amino salt form of gymnemic acid can be amono-alkyl substituted derivative of the di-amino salt form of gymnemicacid, a di-alkyl substituted derivative of the di-amino salt form ofgymnemic acid, or a tri-alkyl substituted derivative of the di-aminosalt form of gymnemic acid. In yet other embodiments of the presentinvention, the tri-amino salt form of gymnemic acid can be a mono-alkylsubstituted derivative of the tri-amino salt form of gymnemic acid, adi-alkyl substituted derivative of the tri-amino salt form of gymnemicacid, or a tri-alkyl substituted derivative of the tri-amino salt formof gymnemic acid. In further embodiments of the present invention, thetetra-amino salt form of gymnemic acid can be a mono-alkyl substitutedderivative of the tetra-amino salt form of gymnemic acid, a di-alkylsubstituted derivative of the tetra-amino salt form of gymnemic acid, ora tri-alkyl substituted derivative of the tetra-amino salt form ofgymnemic acid. In yet further embodiments of the present invention, thepoly-amino salt form of gymnemic acid can be a mono-alkyl substitutedderivative of the poly-amino salt form of gymnemic acid, a di-alkylsubstituted derivative of the poly-amino salt form of gymnemic acid, ora tri-alkyl substituted derivative of the poly-amino salt form ofgymnemic acid.

The gymnemic acid is present in any amount effective to partially orcompletely block the sensation of sweet taste in a subject for a periodof time. Examples of such amounts include, but are not limited to, thosein the range of about 0.01% to about 25% by weight, about 0.01% to about10% by weight, about 0.01% to about 4% by weight, about 0.05% to about2% by weight, about 0.01% to about 1% by weight, about 0.01% to about0.5% by weight, and about 0.01% to about 0.2% by weight of the totalweight of the lingual delivery form or composition. In certainembodiments, the gymnemic acid can be present in about 0.1% to 5%weight, 0.01 to 1% weight, about 0.01% to 0.5% weight, or about 0.01% to0.2% weight of the lingual delivery form. In terms of absolute amount,the lingual delivery forms and compositions of the present invention maycomprise about 0.1 mg to 200 mg of gymnemic acid, including but notlimited to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, or 200 mg of gymnemicacid. The amount of gymnemic acid in the lingual delivery forms andcompositions of the present invention can vary depending on thecomposition and form of the composition (e.g., non-liquid or liquid). Inthis regard, the amount of gymnemic acid can be varied depending on theuse and desired results. The remaining portion of the lingual deliveryform can include other excipients including, but not limited to,sucrose, glucose, lactose, corn syrup solids, maltodextrin, sorbitol,xylitol, erythritol, and other carbohydrates and polyols. Furthermore,the lingual delivery form can include flavors such as peppermint,spearmint, and menthol.

Many flavors, such as vanilla and chocolate, also require the presenceof sweet taste as a carrier, i.e., the flavor cannot be tasted unlessthe sweet taste is also present. However, mint does not require sweettaste as a carrier, and thus can be tasted and enjoyed without thepresence of a sweet taste. Accordingly, the lingual delivery form mayfurther comprise mint. For example, the mint may be peppermint,spearmint, or menthol. Moreover, while the addition of mint to gymnemicacid cannot block the bitter taste, to the extent there is any remainingbitterness upon administration of the lingual delivery form comprisinggymnemic acid and a form of zinc, the mint will mask or block it.

In certain embodiments, the compositions of the present inventioncomprise gymnemic acid, a form of zinc, and at least one sour tasteinhibitor. Any sour taste inhibitor known in the art may be used. Anexample of such a sour taste inhibitor includes, but is not limited to,miraculin.

The lingual delivery forms and the compositions of the present inventioncomprising gymnemic acid and a form of zinc may also further comprise atleast one bitter taste inhibitor. Any bitter taste inhibitor known inthe art may be used. Examples of such bitter taste inhibitors include,but are not limited to sodium salts.

The at least one bitter taste inhibitor, when included, is present inany amount effective to reduce or eliminate the bitter taste of thegymnemic acid. In certain embodiments, the bitter taste inhibitor ispresent in an amount in the range of from about 1 to about 200 mg.Specific examples of such amounts include, but are not limited to, about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 150, or 200 mg of bitter tasteinhibitor. For example, a form of zinc, such as a zinc salt may bepresent as a bitter taste inhibitor in an amount of, for example, 0.2%,1%, 2%, or 5% by weight. In certain other embodiments, when the bittertaste inhibitor is a zinc salt, the percentage by weight of zinc ion isin the range of either 0.01% to 100%, or 1.0% to 75%, or 1.5% to 70%, or2% to 65%, or 2.5% to 50%. The percentage weight of zinc ion is definedas the proportion of zinc ion to the sum of zinc ion plus gymnemic acid.Gymnemic acid content is determined according to the methods describedabove and zinc ion is determined according to zinc ion as percentage ofthe zinc form. For example, Zn² is 40% of the molecular weight of zincsulfate (ZnSO₄), therefore 10 mg of zinc sulfate is equivalent to 4 mgZn².

In certain embodiments, the combination of the gymnemic acid and form ofzinc act synergistically in terms of the length of the resultantsweetness blockade. In certain embodiments, such synergisticcombinations will result in the partial or complete inhibition of thesensation of sweet taste in a subject for about 30 minutes or more,about 60 minutes or more, about 90 minutes or more, or about 120 minutesor more. In certain embodiments, the combination of the gymnemic acidand form of zinc surprisingly act synergistically, prolonging thepartial or complete sweetness blockade in a subject for periods longerthan gymnemic acid administered to the oral cavity in the absence of atleast one further sweet taste inhibitor and/or at least one sour tasteinhibitor and/or at least one bitter taste inhibitor. Surprisingly,applicants found that the combination of the gymnemic acid (15 mg) andZnSO₄.7H₂0 (107 mg) resulted in complete blockade of sweet taste at 60minutes following administration, where at 60 minutes partial recoveryof sweet taste sensation had been found with administration of gymnemicacid alone.

In certain other embodiments, when the at least one further sweetnessinhibitor is a zinc salt, the percentage by weight of zinc ion is in therange of either 0.01% to 100%, or 1.0% to 75%, or 1.5% to 70%, or 2% to65%, or 2.5% to 50%. The percentage weight of zinc ion is defined as theproportion of zinc ion to the sum of zinc ion plus gymnemic acid, andwhere zinc ion and gymnemic acid content are determined according to themethods described above.

The methods of the present invention comprise administering the lingualdelivery forms and compositions to a subject. In one embodiment, themethod of administering the above lingual delivery forms andcompositions to the subject results in a reduced appetite in the subjectfor sweet tasting foods and drinks In another embodiment, the method ofadministering the above lingual delivery forms and compositions to thesubject results in reduced calorie intake in the subject, since thesubject no longer craves sweet tasting foods. In another embodiment, themethod of administering the above lingual delivery forms andcompositions to the subjects results in reduced dental caries in thesubject, since the subject consumes less sweet tasting foods and drinksIn certain embodiments, the methods of the present invention includecontacting (e.g., disposing, chewing, sucking, licking, or the like) anoral cavity of a subject with an amount of a lingual delivery form orcomposition. The oral cavity can include the tongue, inside of themouth, the buccal cavity, under the tongue, and the like. In yet otherembodiments, the composition is contacted with the oral cavity for atime period of about 1 to 10 minutes. In further embodiments, thecomposition can be contacted with the oral cavity multiple times, suchas by chewing separate pieces of gum at various time frames during atime period (e.g., multiple hours, day, etc.).

In certain embodiments, the methods of the present invention provide fora sweetness blockade in the subject for a time period of about 30 to 120minutes or about 60 minutes to 120 minutes upon contacting thecomposition with the oral cavity of the subject. In an embodiment, thetime frame can start from the time the composition is no longer in theoral cavity, for example, when the gum is removed or the lozenge hasundergone full dissolution.

This invention is further illustrated by the following examples, whichshould not be construed as limiting. The examples are set forth so as toprovide those of ordinary skill in the art with an illustrativedisclosure and description of how to perform the methods and use thecompounds disclosed and claimed herein. Those skilled in the art willrecognize that the invention may be practiced with variations on thedisclosed structures, materials, compositions and methods, and suchvariations are regarded as within the ambit of the invention. Unlessindicated otherwise, parts are parts by weight, temperature is in ° C.,and pressure is at or near atmospheric. Standard temperature andpressure are defined as 20° C. and 1 atmosphere.

EXAMPLES Formulation Examples Formulation FLLC-F27c 4 mg (ExtendedRelease Formulation)

Weight 40X 100X 240X Excipient Name % Ratio (grams) grams grams gramsActive (Four-ccl- 0.800 0.0040 0.160 0.400 0.960 15B) [gymnemic acid]Sorbitol (Parateck S1 62.100 0.3105 12.420 31.050 74.520 150) Erythritol30.000 0.1500 6.000 15.000 36.000 Zinc Gluconate 1.300 0.0065 0.2600.650 1.560 Ferminich 2.400 0.0120 0.480 1.200 2.880 PeppermintFerminich Mint 2.400 0.0120 0.480 1.200 2.880 Magnesium Stearate 1.0000.0050 0.200 0.500 1.200 Total 100.000 0.5000 20.000 50.000 120.000

Comments

Used a 10 mm Concave die to make a 500 mg tablet.

Formulation Procedure Used:

Co-milled the active with 1 gram of Erythritol and Zinc Gluconate to afine homogenous powder Sieved remaining excipients through 30 meshscreen. Then combined all excipients except for magnesium stearate.Blended for 30 minutesAdded magnesium stearateBlended for 1 minutePressed formulation into tablets

Taste Blocking Examples

A standard method was developed to quantify the duration of sweet tasteblockade for the gymnemic acid compositions of the present invention.The gymnemic acid used in the following examples was partially purifiedfrom a crude extract of Gymnema sylvestre leaves and was determined tobe a mixture of gymnemic acids (81% purity), which was primarily GA 1and GA 2, with lesser amounts of GA 3 and GA 4 and also including a GAacetate/benzoate diester (i.e., GA 34—Gymnemoside C). In all cases,sucrose was used as the sweetener in sweet taste blockadequantification. Thus, 10%, 8%, 6%, 4%, and 2% (w/v) sucrose solutions inreverse osmosis (RO) purified water were freshly prepared and, at thebeginning of each experiment, 15 mL samples of each sucrose solutionwere used to calibrate sensory panelist on sweetness intensity. Thesensory panelist is described as a person with training in sensoryevaluation with at least 1 year of experience as a sensory panelist inthe area of gustatation, and preferably with training in descriptiveanalysis. Standard scaling methodology was used for quantification ofsweetness intensity (SI) on the following scale:

-   -   10% sucrose=10,    -   8% sucrose=8,    -   6% sucrose=6,    -   4% sucrose=4,    -   2% sucrose=2, and    -   0% sucrose=0.

Following panelist calibration with the sucrose reference standards, thepanelist rinsed their mouth with 15 mL RO water and the sweetnessinhibitor sample in 15 mL RO water was then immediately taken into themouth and gently agitated for 5 minutes. The sweet taste inhibitorsample was then expectorated and a 15 mL sample of the 10% sucrosereference solution was then immediately re-tasted, perceived SI within15 seconds was rated on the 0-10 scale, the sample expectorated, and themouth rinsed vigorously with 15 mL RO water. The 10% sucrose sample wasthen re-tasted every 15 min and SI rated. The panelist was asked to makecomments on the observations of non-sweet taste attributes at eachsucrose reference tasting interval. SI results in experiments by thisstandard protocol are simple means of the SI ratings.

Gymnemic acid exhibits significant bitter off-taste. Scaling methodologywas employed to quantify the bitterness of gymnemic acid alone and incombination with a variety of substances in effort to identify gymnemicacid compositions with diminished or eliminated bitter taste. In thismethodology, sucrose was used as the scaling reference. Thus, as above,bitterness ratings of 10, 8, 6, 4, 2, and 0 are indicative ofperceptions of bitter taste equivalent in intensity to sweet tasteperceptions of 10, 8, 6, 4, 2, and 0% sucrose, respectively.

Comparative Example 1—Sweetness Inhibition of Gymnemic Acid (15 mgDosage)

Gymnemic acid was evaluated to quantify the duration of its sweet tasteinhibition in order to determine a baseline value against which tocompare the following inventive examples. Results obtained aresummarized in Table 1.

TABLE 1 Time (min) SI Comments & Observations 0 0 No sweetness; strongbitterness. 15 0 No sweetness; medium bitterness. 30 0 No sweetness;weak/medium bitterness. 45 1 Faint sweetness; weak bitterness. 60 1Faint sweetness; faint bitterness. 75 2 Weak sweetness; no bitterness.90 3 Weak sweetness; no bitterness. 105 7 Medium to strong sweetness; nobitterness. 120 10 Strong sweetness; no bitterness.

Comparative Example 2—Sweetness Inhibition of Lactisole (3 mg Dosage)

Lactisole was evaluated to quantify the duration of its sweet tasteinhibition in order to determine its potential value in combination withgymnemic acid. Lactisole differs from gymnemic acid as a sweetnessblocker, for example, the sweetness blockade provided by lactisole doesnot linger after exposure to the tongue. However, surprisingly, it wasobserved that following exposure of the oral cavity to lactisole, nosweet taste inhibition was observed, not even when the 10% sucrosereference was tasted immediately afterlactisole expectoration.

Results obtained are summarized in Table 2.

TABLE 2 Time (min) SI Comments & Observations 0 12 Very strong sweetnessgreater than 10% sucrose reference; no bitterness. 15 10 Strongsweetness; no bitterness. 30 10 Strong sweetness; no bitterness. 45 10Strong sweetness; no bitterness. 60 10 Strong sweetness; no bitterness.75 10 Strong sweetness; no bitterness. 90 10 Strong sweetness; nobitterness. 105 10 Strong sweetness; no bitterness. 120 10 Strongsweetness; no bitterness.

Example 1—Sweetness Inhibition of Blend of Gymnemic Acid (15 mg) andLactisole (3 mg)

A gymnemic acid/lactisole blend was evaluated to quantify the durationof its sweet taste inhibition. Results obtained are summarized in Table3.

TABLE 3 Time (min) SI Comments & Observations 0 3 Weak sweetness; strongbitterness. 15 2 Weak sweetness; strong bitterness. 30 2 Faintsweetness; strong bitterness. 45 1 Faint sweetness; strong bitterness.60 1 Faint sweetness; medium/strong bitterness. 75 1 Faint sweetness;medium/strong bitterness. 90 2 Weak sweetness; medium bitterness. 105 4Weak/medium sweetness; medium bitterness. 120 5 Medium sweetness; mediumbitterness.Surprisingly, when the 10% sucrose reference sample was tastedimmediately following oral cavity treatment with the gymnemicacid/lactisole blend, it was observed to have weak to moderate intensitysweet taste and not tasteless, as when pre-treatment was carried outwith gymnemic acid alone. This initial sweetness is of significantbenefit for improvement of the overall sensorial experience of a sweettaste inhibitory composition and is not possible with gymnemic acid orother gymnemic acid formulations. Also, surprisingly, it was observedthat while lactisole itself caused no sweetness inhibition followingexpectoration, the gymnemic acid/lactisole blend caused a prolongedduration of sweet taste inhibition relative to the duration of sweettaste inhibition with gymnemic acid alone. Thus, though the biochemicalmechanism is not clear, it is apparent that lactisole in combinationwith gymnemic acid results in a synergistic sweet taste inhibitoryeffect, one where weak sweet taste is observed in the first 30 minutesfollowing gymnemic acid/lactisole pre-treatment. This effect may be ofvalue to improve the overall sensory experience of sweet tasteinhibitory products formulated to provide prolonged blockade ofsweetness.

Comparative Example 3—Sweetness Inhibition of Zinc Sulfate Heptahydrate(ZnSO₄.7H₂0, 107 mg Dosage)

ZnSO₄.7H₂0 was evaluated to quantify the duration of its sweet tasteinhibition in order to determine its potential value in combination withgymnemic acid. Surprisingly, it was observed that ZnSO₄ 7H₂0, likegymnemic acid, does cause a prolonged period of sweet taste inhibition,though not nearly as prolonged as is the case with gymnemic acid, assweetness sensitivity was 100% restored after 60 minutes. Resultsobtained are summarized in Table 4.

TABLE 4 Time (min) SI Comments & Observations 0 0 No sweetness orbitterness; weak astringency. 15 2 Weak sweetness; no bitterness; weakastringency. 30 5 Medium sweetness; no bitterness; faint astringency. 458 Strong sweetness; no bitterness; faint astringency. 60 10 Strongsweetness; no bitterness or astringency. 75 10 Strong sweetness; nobitterness or astringency. 90 10 Strong sweetness; no bitterness orastringency. 105 10 Strong sweetness; no bitterness or astringency. 12010 Strong sweetness; no bitterness or astringency.

Example 2—Sweetness Inhibition of Blend of Gymnemic Acid (15 mg) andZnSO₄ 7F1₂0 (107 mg)

A blend of gymnemic acid/ZnSO₄.7H₂0 was then evaluated for duration ofsweet taste blockade. Results are summarized in Table 5.

TABLE 5 Time (min) SI Comments & Observations 0 0 No sweetness orbitterness; weak astringency. 15 0 No sweetness or bitterness; faintastringency. 30 0 No sweetness or bitterness; faint astringency. 45 0 Nosweetness or bitterness; faint astringency. 60 0 No sweetness orbitterness; faint astringency. 75 1 Faint sweetness; no bitterness orastringency. 90 2 Faint sweetness; no bitterness or astringency. 105 3Weak sweetness; no bitterness or astringency. 120 4 Medium sweetness; nobitterness or astringency.Surprisingly, complete blockade of sweet taste was still observed at 60minutes while partial recovery occurs by that time when gymnemic acid isused alone. Thus, although the mechanistic process is unclear, thecombination of ZnSO₄ 7H₂0 with gymnemic acid clearly possesses asynergistic sweet taste inhibitory effect.

Comparative Example 4—Sweetness Inhibition of Miraculin (80 mg Dosage)

Miraculin was evaluated to quantify the duration of its sweet tasteinhibition in order to determine its potential value in combination withgymnemic acid. No sweet taste inhibitory effect was observed followingmiraculin pre-treatment of the oral cavity. Results obtained aresummarized in Table 6.

TABLE 6 Time (min) SI Comments & Observations 0 10 Strong sweetness andno other taste. 15 10 Strong sweetness and no other taste. 30 10 Strongsweetness and no other taste. 45 10 Strong sweetness and no other taste.60 10 Strong sweetness and no other taste. 75 10 Strong sweetness and noother taste. 90 10 Strong sweetness and no other taste. 105 10 Strongsweetness and no other taste. 120 10 Strong sweetness and no othertaste.

Example 3—Sweetness Inhibition of Blend of Gymnemic Acid (15 mg) andMiraculin (80 mg)

Even though no sweet taste inhibitory effect was observed, miraculin wasnonetheless evaluated in combination with gymnemic acid to determine ifany prolongation of gymnemic acid sweet taste inhibition duration wouldbe observed. It was observed that miraculin did prolong the duration ofgymnemic acid sweet taste blockade. As such, miraculin in combinationwith gymnemic acid results in a synergistic inhibitory effect on sweettaste. Results are summarized in Table 7.

TABLE 7 Time (min) SI Comments & Observations 0 0 No sweetness; weakbitterness and some sourness. 15 0 No sweetness; weak bitterness. 30 0No sweetness and no bitterness. 45 0 No sweetness and no bitterness. 601 Very faint sweetness, just above threshold and no other taste. 75 1Very faint sweetness, just above threshold and no other taste. 90 2 Weaksweetness and no other taste. 105 3 Weak sweetness and no other taste.120 5 Medium sweetness; no bitterness.

Example 4—Sweetness Inhibition of Blend of Gymnemic Acid (15 mg),Lactisole (3 mg), and ZnSO₄.7H₂0 (107 mg)

As demonstrated above, lactisole and ZnSO₄ 7H₂0, when used independentlyin combination with gymnemic acid, exhibit synergy in sweetnessinhibition. A ternary blend composition containing both of these sweettaste inhibitors in combination with gymnemic acid was evaluated todetermine if increased synergy would be present. Results are summarizedin Table 8.

TABLE 8 Time (min) SI Comments & Observations 0 0 No sweetness orbitterness at all; only medium/strong astringency. 15 0 No sweetness orbitterness at all; only medium/strong astringency. 30 0 No sweetness orbitterness at all; only medium astringency. 45 1 Very faint sweetness;no bitterness; only weak/medium astringency. 60 1 Very faint sweetness;no bitterness; only weak/medium astringency. 75 2 Weak sweetness; nobitterness; only weak/medium astringency. 90 2 Weak sweetness; nobitterness; only weak astringency. 105 3 Weak sweetness, but slightly >than @ 90 min; no bitterness; only weak astringency. 120 4 Weak/mediumsweetness slightly > than @ 105 min; no bitterness and weak astringency.

A comparison of the sweet taste inhibition results of this ternary blendwith the results of Examples 1 and 2 show that increased synergy is notobserved. However, this ternary blend formulation is clearlyadvantageous in that the synergies present in the gymnemic acid binaryblends with lactisole and ZnSO₄ 7H₂0 remain, while full inhibition ofthe bitter off-taste of gymnemic acid is realized.

Gymnemic acid, when used in aqueous compositions or formulated inlozenges or tablets, exhibits weak to medium or even strong bitteroff-tastes, which is a limitation to its effective use in formulationsdesigned to aid consumers in controlling their intake of caloric sweetproducts.

Comparative Example 5—Bitterness of Gymnemic Acid (15 mg Dosage)

A solution of 15 mg gymnemic acid in 15 mL RO water was evaluated andfound to have a bitterness score of 10 on a 15-point scale forbitterness.

Example 5—Bitterness of Blend of Gymnemic Acid (15 mg) and ZnSO₄ 7H₂0(107 mg)

A solution of 15 mg gymnemic acid in 10 mL RO water was combined with asolution of 107 mg ZnSO₄ 7H₂0 in 5 mL RO water and evaluated. It wasfound to have a bitterness score of 0. Aqueous solutions containing 60,34, 19, 10.7, 6 and 3.4 mg, respectively, of ZnSO₄ 7H₂0 in 5 mL RO waterwere combined with 15 mg gymnemic acid in 10 mL RO water samples. Theresultant mixtures exhibited bitterness intensities of 0, 0, 0, 1, 4 and7, respectively. Thus, these gymnemic acid/ZnSO₄ 7H₂0 compositionsexhibit an absence of bitterness when the ZnSO₄ 7H₂0 concentrations areequal to or greater than approximately 0.6 mg/mL (2 mM).

It should be emphasized that the above-described embodiments of thepresent disclosure are merely possible examples of implementations, andare merely set forth for a clear understanding of the principles of thisdisclosure. Many variations and modifications may be made to theabove-described embodiment(s) of the disclosure without departingsubstantially from the spirit and principles of the disclosure. All suchmodifications and variations are intended to be included herein withinthe scope of this disclosure.

1. A composition comprising gymnemic acid and at least one form of zinc.2-25. (canceled)